Obesity emerges from a complex interplay of factors, including imbalanced interoception, genetic predisposition, and environmental cues, which ultimately disrupt body weight homeostasis1. While much research has concentrated on strategies to suppress appetite for sustained weight loss, insufficient attention has been given to counterregulatory mechanisms that promote energy expenditure. Here, we show that chronic inhibition of GABAergic neurons in the dorsal raphe nucleus and ventrolateral periaqueductal gray (DRN/vlPAGVGAT) reduces body weight in diet-induced obese (DIO) male mice. In this study, molecular profiling and in-situ hybridization in rodent and human brains revealed that the constitutively activated orphan receptor GPR6 is selectively enriched in DRN/vlPAGVGAT neurons. We next developed and administered a potent and highly selective GPR6 inverse agonist, which significantly prevented weight gain in male mice exposed to a high-fat diet by stimulating brown adipose tissue thermogenesis without affecting appetite. Altogether, this study integrates transcriptomic profiling, high-throughput drug screening and metabolic phenotyping to successfully identify a candidate to treat obesity.
